Alzheimer's disease (AD) is the only leading cause of death with no effective means of slowing its progression. Varying models predict the involvement of diverse neurodegenerative stresses, including amyloid beta (A) peptides, proinflammatory cytokines, oxidative stress, and energetic stress in mediating the pathogenesis of both familial (FAD) and sporadic (SAD) forms of the disease. In spite of decades of active research and a deep molecular understanding of many of the major molecular players in the progression of dementia, there are many areas of confusion. For example, there is good agreement on the fact that excess production of amyloid- is a causative or major contributing factor to the initiation of dementia and most mouse models to study AD utilize the expression of human amyloid precursor protein (APP) with early onset AD mutations (usually along with other mutant human proteins) to generate mice that develop cognitive deficits and at least some aspects of human AD pathology. However, there is still much debate over the actual form of the A that induces the synaptic deficits. In addition, a plethora of neuronal proteins with totally unrelated functions that interact with human A have been identified and elimination of any one of these binding partners alone was sufficient to reduce or eliminate the cognitive deficits when these mice were crossed with an AD mouse model over producing A. No current model can explain how single elimination of the different A binding partners protects against development of A-induced cognitive deficits. We recently showed that very active forms of soluble A consisting of dimers and trimers (Ad/t), as well as proinflammatory cytokines (TNFa, IL-1, IL-6) stimulate NADPH oxidase (NOX) and production of reactive oxygen species (ROS) in neurons through a cellular prion protein (PrPC)-dependent pathway. This pathway stimulated the formation of rod-shaped bundles of 1:1 cofilin:actin (rods), which cause synaptic dysfunction. Formation of rods requires activation (dephosphorylation) of the actin binding protein cofilin as well as its oxidation to form intermolecular disulfide bonds. Rods do not form i response to A or proinflammatory cytokines in PrPC-null neurons, but surprisingly, over expression of PrPC alone is sufficient to induce rods at much higher levels than are induced by A of proinflammatory cytokine treatment. Thus, we have proposed a new model in which multiple receptors can contribute to NOX activation and ROS production through PrPC-interactions in enlarged membrane domains. The triggering of cofilin oxidation to form rods is dependent on achieving a threshold level of ROS and this is why coalescence of many different receptors into signaling complexes contributes to achieving this ROS level. Rods sequester cofilin and can occlude neurites, blocking transport, either of which inhibit normal synaptic function. Using cultured primary neurons and several knock-out or transgenic mouse lines, we propose to determine (1) if the relative rod-inducing activities of different forms of A relate t their direct affinity for PrPC, (2) if specific proinflammatory cytokine receptors are required for their rod induction through the PrPC- dependent pathway, (3) if the PrPC-pathway functions in both axons and dendrites and if mislocalization of rod signaling components occurs between compartments, and (4) the role in cofilin activation played by three likely components of the cytoplasmic domain of PrPC-signaling complexes.